CK2β regulates thrombopoiesis and Ca2+-triggered platelet activation in arterial thrombosis

Abstract

Platelets, anucleated megakaryocyte (MK)-derived cells, play a major role in hemostasis and arterial thrombosis. Although protein kinase casein kinase 2 (CK2) is readily detected in MKs and platelets, the impact of CK2-dependent signaling on MK/platelet (patho-)physiology has remained elusive. The present study explored the impact of the CK2 regulatory β-subunit on platelet biogenesis and activation. MK/platelet-specific genetic deletion of CK2β ( ) in mice resulted in a significant macrothrombocytopenia and an increased extramedullar megakaryopoiesis with an enhanced proportion of premature platelets. Although platelet life span was only mildly affected, MK displayed an abnormal microtubule structure with a drastically increased fragmentation within bone marrow and a significantly reduced proplatelet formation in vivo. In platelets, tubulin polymerization was disrupted, resulting in an impaired thrombopoiesis and an abrogated inositol 1,4,5-triphosphate receptor-dependent intracellular calcium (Ca) release. Presumably due to a blunted increase in the concentration of cytosolic Ca, activation-dependent increases of α and dense-granule secretion and integrin αβ activation, and aggregation were abrogated in platelets. Accordingly, thrombus formation and stabilization under high arterial shear rates were significantly diminished, and thrombotic vascular occlusion in vivo was significantly blunted in mice, accompanied by a slight prolongation of bleeding time. Following transient middle cerebral artery occlusion, mice displayed significantly reduced cerebral infarct volumes, developed significantly less neurological deficits, and showed significantly better outcomes after ischemic stroke than mice. The present observations reveal CK2β as a novel powerful regulator of thrombopoiesis, Ca-dependent platelet activation, and arterial thrombosis in vivo.

LipidCreator workbench to probe the lipidomic landscape

“…For further validation of LipidCreator, we investigated lipid mediators and their precursor ions during human platelet activation. Platelets are essential for maintaining vascular integrity and hemostasis and are further critically involved in vascular inflammation, as well as acute arterial thrombotic occlusion following the rupture of atherosclerotic plaques 55,56 . Lipid mediators have important functions in platelet physiology, signaling and energy production 57 .…”

Impact ofItga2-Gp6-double collagen receptor deficient mice for bone marrow megakaryocytes and platelets

“…The blood-bone marrow barrier is of special interest for this transition, as under healthy conditions we do not observe that platelets become prematurely (or ectopically) released into the bone marrow cavity rather than across the endothelial barrier into the blood stream. Some mice that lack regulatory proteins have been described to prematurely release platelet: WAS [27], CK2B [28], or ADAP [29]. The underlying mechanism, however, remains poorly described.…”

Imaging platelet biogenesis in vivo

“…Nevertheless, two‐photon microscopy of cranial bone marrow has become the method of choice to study platelet biogenesis in vivo. At the ISTH conference in Berlin several studies were presented that utilized 2PM to assess the effects of gene deficiencies on platelet biogenesis …”

“…Münzer et al. analyzed mice lacking the casein kinase 2β, a serine threonine kinase expressed in MKs and platelets, and observed an abnormal microtubule structure in vitro and enhanced proportion of premature platelets that were released into the BM cavity as observed by 2PM . resembling the defective MK morphology of mice lacking the small GTPases Cdc42 and Rac1 .…”